Bioactive Lipids - Springer

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1 Bioactive Lipids 2 metabolic effects of short-chain fatty acids have 2.1 Introduction been discussed in other parts of this book. Several groups of lipids have been shown to pro- vide health benets either through modication of tissue fatty acid composition or induction of 2.2 Butyric Acid cell signaling pathways. While some health benets are derived from consumption of short- Butyrate is commonly found as part of the lipid to medium-chain fatty acids, evidence suggests component of dairy milk but is also one of the that the polyunsaturated fatty acids (PUFAs) are main by-products (others are acetate and propi- the most important bioactive lipids. PUFAs are onate) of ber fermentation in the colon and has found mostly in plant seed oils and are important been shown to induce various benecial meta- substrates for the biosynthesis of cellular hor- bolic effects. Butyrate has been shown in vivo to mones (eicosanoids) and other signaling com- be a stimulant of normal colonic cell prolifera- pounds that modulate human health. The tion but can also inhibit growth and proliferation benecial health effects of PUFAs seem to be of colon cancer cell lines. Other suggested health dependent on their isomer conguration as the benets of butyrate include: cis-isomer is the predominant bioactive form. Substrate used for growth and regeneration of Moreover, fatty acids in the cis-conguration cells in large intestine. have a rigid nonlinear structure, which enhances Anti-colon cancer properties probably through membrane uidity when incorporated into cells. enhanced apoptosis of mutant colonic cells. Increased membrane uidity enhances cell to cell Animal experiments also showed benecial communication and helps maintain normal effect on the growth of cells in the small homeostasis or prevent the development of meta- intestine. bolic disorders. Therefore, this chapter will focus Increased thermogenesis to increase energy mostly on PUFAs but with brief discussions on a expenditure, which contributes to reduced short-chain fatty acid (butyric acid) and medium- body weight and other markers of metabolic chain fatty acids. Detailed descriptions of the syndrome. R.E. Aluko, Functional Foods and Nutraceuticals, Food Science Text Series, 23 DOI 10.1007/978-1-4614-3480-1_2, Springer Science+Business Media, LLC 2012

2 24 2 Bioactive Lipids long-chain fatty acids. One solution to this prob- 2.3 Medium-Chain Fatty Acids lem has been the development of oils that contain triglycerides with combinations of MCFAs and These are fatty acids that contain 810 carbon long-chain fatty acids (LCFAs) esteried to the atoms, mainly caprylic (C8:0) and capric (C10:0) glycerol backbone; such oils are called medium- acids, which are metabolized differently when and long-chain triglycerides (MLCT), which compared to long-chain fatty acids (14 or more have received regulatory approval in Japan for carbon atoms). Medium-chain triglycerides use in human foods. In type 2 diabetes, diet sup- (MCTs) contain medium-chain fatty acids plementation with 7% (w/w of diet) MLCT (con- (MCFAs) esteried to glycerol backbone and are tains ~13% MCFAs and ~87% LCFAs) led to usually completely hydrolyzed to yield the free signicant decreases in mesenteric fat weight and fatty acids by lipases present in the gastrointesti- postprandial insulin levels. Increase in mesen- nal tract. When absorbed directly, MCTs enter the teric fat weight has been associated with insulin blood circulatory system through the portal vein resistance; hence, the effect of MLCT has poten- and carried to the liver where they are oxidized to tial health benets for blood glucose manage- ketones. This is because in the mitochondria, ment. The MLCT diet-induced higher plasma transport of MCTs does not require carnitine levels of adiponectin was inversely correlated palmitoyltransferase, a rate-limiting enzyme of with mesenteric fat weight and plasma insulin b-oxidation. The mostly catabolic fate of MCFAs level. The observed increased levels of plasma is evident by the fact that dietary MCTs reduce adiponectin may be because MCFAs can sup- blood triglyceride levels during human interven- press adipocyte hypertrophy. Adiponectin is tion trials. Thus, dietary MCTs induce thermo- known to increase AMPK, an enzyme that genesis and do not contribute to weight gain since increases muscle sensitivity to glucose uptake. they are not deposited in the adipose tissue. This has been demonstrated in diet intervention trials involving hypertriglyceridemic human subjects 2.4 Long-Chain Fatty Acids where MCTs reduced body mass index, hip cir- cumference, waist-hip ratio, total abdominal fat, These are fatty acids with 14 or more linearly visceral fat, body fat mass, and waist circumfer- arranged carbon atoms and may be saturated ence. MCT diets also reduced blood levels of sev- (no double bonds) or unsaturated (one or more eral types of LDL as well as LDL-cholesterol to double bonds). These fatty acids are found mostly greater extent than traditional oil that contained as components of the triglycerides of edible oils long-chain triglycerides. Therefore, MCTs may and fats. be used as a means of preventing and treatment of obesity, though the exact molecular mechanism of action has not been fully elucidated apart from 2.4.1 Monounsaturated Fatty Acids the thermogenic effects. But MCTs were shown to activate hormone-sensitive lipase and down- Feeding monkeys with a diet rich in oleic acid regulate fatty acid synthase, which led to increased (60% of the fatty acids) led to up to 17% reduction lipolysis and reduced fat accumulation, respec- in plasma total cholesterol concentrations when tively, in white adipose tissue. And MCTs are compared to the group that was fed a diet that able to upregulate expression of lipoprotein was predominantly rich in saturated fatty acids. lipase, which is the major enzyme that is respon- Substitution of dietary monounsaturated for sible for lipolysis. It should be noted that MCT saturated fatty acids resulted in a 28% decrease in oils are difcult to use as cooking oils because the the Apolipoprotein B (ApoB) levels, which is presence of medium-chain fatty acids causes the due to lower production rates of LDL ApoB. oil to have lower smoke point than oils containing There were also less amounts of circulating LDL

3 2.4 Long-Chain Fatty Acids 25 use of stearic acid (same carbon length but no double bond) had no effect on SOCE. Oleic acid blocks Ca2+ entry by binding to membrane mole- cules at the outer side of the membrane; there- fore, it is possible that the structural conformation arising from the presence of a single double bond Fig. 2.1 Structural conguration of cis-oleic acid enhances interaction with the membrane surface. In contrast, conformation of the saturated stearic particles in the plasma. Oleic acid (Fig. 2.1) has acid seems to be incompatible with the required also been proposed to have a potential role in binding protocol at the surface of the cell decreasing brain-related disorders such as demen- membrane. tia and Alzheimers disease. Among unsaturated fatty acids tested, oleic acid had the highest in vitro inhibition of prolyl endopeptidase (PEP), 2.4.2 Polyunsaturated Fatty an enzyme that is believed to have a role in amy- Acids (PUFA) loid formation in the brain. Afnities of fatty acids for PEP as measured by inhibition constants Epidemiological studies have showed a low inci- (inversely related to afnity) were ~27, 51, 89, dence of coronary heart diseases (CHD) in the 91, and 248 mM, respectively, for oleic, linoleic, Inuit population even though they consume a diet docosahexaenoic, arachidonic, and eicosapen- that is high in saturated fatty acid content. The low taenoic acids. PEP levels have been found to be incidence of CHD was associated with the high upregulated in Alzheimers disease patients, and levels of n-3 PUFAs that are also present in the rat experiments have shown improved cognitive mostly marine-product-laden diet of the Inuit. It is functions when administered with PEP inhibi- also known that a diet with high levels of linoleic tors. While in vivo studies are required to deter- and linolenic acids has better cholesterol-lower- mine exact mechanisms of action, preliminary ing effects when compared with a diet rich in satu- work suggests that consumption of oleic-acid- rated fatty acids. Unlike monounsaturated fats, a rich diets could have benecial effects on brain polyunsaturated-rich diet can decrease ApoB functions by reducing activity of PEP. levels by a combination of reduced production Oleic acid has also been shown to have a and increased catabolism. ApoB is the main lipo- potential role in the therapeutic management of protein in low-density lipoproteins and is a colorectal cancer, one of the most common types marker of atherosclerosis and increased risk of of tumors, especially in western countries. The cardiovascular damage because it is the main basic mechanism involves inhibition by oleic trafcker of cholesterol in the blood circulatory acid of the store-operated Ca2+ entry (SOCE) pro- system. By decreasing blood circulating levels of cess that controls the Ca2+ inux pathway. ApoB, certain PUFAs can provide protection Operation of the SOCE is believed to be involved against certain cardiovascular diseases that arise in several cellular and physiological processes from excess levels of vascular cholesterol. including cell proliferation. Therefore, attenua- Increased dietary consumption of PUFAs is also tion of the SOCE process by oleic acid could associated with decreased blood levels of media- reduce Ca2+ inux into cells and diminish or tors of lipid-induced insulin resistance, increased eliminate tumor cell proliferation. Oleic acid is insulin sensitivity, and enhanced leptin levels. able to block Ca2+ entry into cells, probably The high plasma leptin levels reduces food intake through free carboxylate-mediated metal chela- due to appetite dampening effects. High levels of tion; this is because methylated oleic acid had no sh consumption (contains high PUFA levels) inhibitory effect on SOCE. Structural conforma- have been associated with improved immune tion of the fatty acid also seemed important con- response such as reduced risk of asthma-related tributory effect to inhibitory properties because symptoms and lower rate of allergic sensitization

4 26 2 Bioactive Lipids in addition to decreased levels of proinammatory 2.4.3 Omega-3 and Omega-6 compounds such as C-reactive proteins, interleu- Fatty Acids kin-6, and prostaglandins (PG). In fact, lack of sh consumption during childhood has been The simplest omega-6 fatty acid is linoleic acid linked to increased risk of asthma development. (C18:2), while linolenic acid (C18:3) is the sim- In general, long-chain PUFAs act as antihy- plest omega-3 fatty acid. Both fatty acids have pertensive agents and reduce the risk for adverse been reported to protect against cardiovascular cardiovascular events by enhancing production and inammatory diseases, though linolenic acid of vasodilatory PGs such as PG1 and PG2. For has greater health benets. Typical examples of example, the metabolic products of linoleic acid chronic diseases that have inammation compo- (gamma-linolenic acid, GLA, and dihomo-GLA) nent and could benet from increased dietary are activators of PG1 and PG2 syntheses and have intake of omega-3 and omega-6 fatty acids been found to prevent elevated blood pressure include lupus, diabetes, psoriasis, obesity, that is associated with consumption of saturated Crohns, rheumatoid arthritis, cystic brosis, fatty acids. Eicosapentaenoic acid (EPA) and Alzheimers, and multiple sclerosis. While less docosahexaenoic acid (DHA) are PUFAs that can effective than oleic acid, the omega fatty acids reduce blood pressure and blood viscosity by have been shown to reduce in vitro activity of enhancing formation of PGI3 (a vasodilator and PEP, an enzyme with potential role in the patho- platelet anti-aggregator) and inhibiting thrombox- genesis of brain diseases. It has been documented ane A2 (TXA2, a potent vasoconstrictor and plate- that blood levels of omega-3 fatty acids are let aggregator). PUFAs also work as inhibitors of inversely proportional to the risk of adverse car- angiotensin-converting enzyme (ACE), a major diovascular events such as stroke and sudden enzyme responsible for increased formation of death. In animal experiments, the ratio of omega-3 angiotensin II (a potent vasoconstrictor). The (n-3) to omega-6 (n-6) was an important determi- antihypertensive effects of PUFAs have also been nant of ultimate health benets. A higher ratio shown to be associated with upregulation of (more n-3 and less n-6) in the diet is more desir- endothelial nitric oxide production, and hyper- able as a means of improving human health such tensive patients have been shown to have low lev- as reduced weight of intra-abdominal fat, adipo- els of PUFAs. The high level of PUFAs in human cyte size, and normalization of heartbeat. This is milk has been associated with reduced risk of because n-3 PUFAs are usually converted to anti- developing hypertension in adulthood when com- inammatory eicosanoids while n-6 PUFAs are pared to formula-fed infants that consume less converted to proinammatory eicosanoids. Thus, amounts of PUFAs. By suppressing hyperten- high levels of dietary n-3 PUFAs enhance the sion, PUFAs can also inhibit development of pro- bodys ability to reduce damaging inammatory teinuria (a marker of kidney damage) and prevent conditions that are known to be responsible for excessive proliferation of vascular smooth mus- the initiation and growth of chronic diseases such cle cells through suppression of TGF-b synthesis. as cancer, kidney malfunction, diabetes, and car- TGF-b is found in elevated concentrations in diovascular disorders. A human interventional hypertensive patients, and interaction with angio- trial involving >2,800 patients that survived a tensin II leads to increased synthesis of extracel- recent myocardial infarction (MI) showed that lular matrix proteins within the kidney and aorta. consumption of 1 g omega-3 fatty acid on a daily Therefore, high levels of TGF-b promote renal basis led to signicant reduction in the cumula- scarring and pathological progression of end- tive rate of all-cause death and nonfatal MI. stage renal disease in hypertensive and diabetic Specically, combinations of docosahexaenoic patients. acid (DHA) and eicosapentaenoic acid (EPA) However, there are other various types of with a-linolenic acid can lower the risk of fatal benecial PUFAs, mostly the omega-3 (n-3) and ischemic heart disease in older adults. Fish oil omega-6 (n-6) fatty acids as well as the conju- contains a high n-3:n-6 ratio and has been shown gated fatty acids. to decrease serum triglyceride and cholesterol

5 2.4 Long-Chain Fatty Acids 27 12 9 COOH Linoleic acid (omega-6) 18 15 12 9 COOH Linolenic acid (omega-3) 18 COOH Docosahexaenoic acid (omega-3) 22 19 16 13 10 7 4 22 COOH Docosapentaenoic acid (omega-3) 19 16 13 10 7 17 14 11 8 5 20 COOH Eicosapentaenoic acid (omega-3) Fig. 2.2 Structural congurations of polyunsaturated fatty acids showing number of double bonds and position of the omega double bond (double bond nearest to the w-carbon atom) levels. However, during clinical trials, the total when compared to women not on the pill. amount of sh oil consumed was a more impor- Testosterone is also known to decrease DHA syn- tant determinant of health benets than the ratio thesis, which may be responsible for the reduced of n-3 to n-6. Fish oil is also able to lower blood conversion of ALA to DHA in men. However, pressure in hypertensive patients. The health this effect (conversion of ALA to DHA) is not benet of sh oil is due mostly to the n-3 PUFA seen in lactating women, and therefore, DHA level, especially EPA and DHA. a-Linolenic acid content of breast milk is inuenced mostly by the (ALA), which is present in vegetable sources fat storage during and before pregnancy, which such as rapeseed, walnuts, axseed, and green reinforces the need for adequate nutrition in leafy products, may be desaturated and elongated women of childbearing age. The lack of ALA to within the human body to yield EPA, docosapen- DHA conversion during lactation may be due to taenoic acid (DPA), and DHA. For example, the action of prolactin (lactating hormone), which daily consumption of 3 g ALA (given as axseed is a known estrogen suppressor. Preformed DHA oil) resulted in 25% and 60% increases in plasma is a critical component of a healthy diet and is levels of DPA and EPA, respectively, but no effect recommended as a means of maintaining physi- on DHA level. Therefore, ALA may serve as a ologically benecial levels. Figure 2.2 shows the dietary precursor of EPA and DPA for vegetarians chemical structures of the most common omega-3 that do not consume sh oil products. However, fatty acids. ALA should not be used as the sole source of n-3 DHA also has anti-inammatory effects PUFAs since current evidence shows that it is through its inhibitory effects on activation of only partially converted to EPA and DPA, but not nuclear factor kappa-B (NF-kB). During high oxi- DHA, especially in men. In women, partial con- dative stress conditions within cells, the high lev- version of ALA occurs probably because of less els of ROS activate NF-kB by releasing it from the b-oxidation and role of estrogens in promoting bound inhibitory protein (IkB). Activated NF-kB fatty acid desaturation. The role of estrogens is then moves into the nucleus where it upregulates evident from the fact that women using oral con- gene expression for several proinammatory traceptive pill that contains 17a-ethynyloestra- cytokines (IL-2, IL-6, and IL-8) and nitric oxide diol had a threefold higher rate of DHA synthesis (NO). DHA acts as an inhibitor of NF-kB by

6 28 2 Bioactive Lipids attenuating oxidative stress; for example, resolvins as well as reduced production of pretreatment of macrophages with DHA has been adhesion molecules (on leukocytes and endothe- shown to reduce NO production. DHA can also lial cells) and proinammatory arachidonic-acid- inhibit NF-kB activation through upregulation of dependent eicosanoid mediators. intracellular antioxidants such as glutathione, Proposed mechanisms for the cardioprotec- which leads to reduction in oxidative stress. In tive effects of omega-3 (n-3) fatty acids: addition to the direct effects, DHA can exhibit 1. Reduction in circulating plasma levels of trig- anti-inammatory effects when it becomes oxi- lycerides and bad lipoproteins. dized to highly potent signaling molecules such as 2. Inhibition of thromboxane A2 synthesis, which resolvins (resolution phase interaction products) leads to decrease in platelet aggregation. and protectins (or neuroprotectin when present in 3. Improved endothelial function (better control the central nervous system), which are called of arterial blood pressure) primarily through docosanoids. DHA has four identied resolvins enhanced NO production. Secondary effects (D1D4), while EPA has two (E1 and E2), all of include improved vasodilation through block- which are generated through lipoxygenase- age of calcium entry into vascular smooth mediated oxidation of the fatty acids. Resolvins muscle, suppression of vasoconstrictor pros- have anti-inammatory activities; they act by tanoids, and reduced plasma epinephrine downregulating activation of NF-kB and removal level. of neutrophils from inammatory sites. Protectins 4. Upregulation and downregulation of genes are DHA-oxidative products formed by peripheral involved in the synthesis of proteins responsi- blood mononuclear cells and CD4 cells in response ble for lipid oxidation and lipid synthesis, to oxidative stress conditions. Protectins are pres- respectively. ent in peripheral blood, lung tissues, neurons, and 5. Prevention of arrhythmias and sudden death. astrocytes. Neuroprotectins have benecial health 6. Decrease in plasma homocysteine levels, a effects such as enhanced nerve regeneration and known risk factor for cardiovascular diseases. reduced leukocyte inltration during inammation. Though mechanism is not fully understood, it Generally, neuroprotectins help to maintain is possible that omega-3 fatty acids modulate homeostasis during aging by reducing pro- gene expression of enzymes involved in homo- apoptotic and proinammatory signaling. As an cysteine metabolism. For example, omega-3 antioxidative agent, synthesis of neuroprotectins fatty acids are known to upregulate activity is enhanced during oxidative stress to protect reti- and mRNA expression of methionine adeno- nal and neuronal cells from apoptosis, probably syl transferase (MAT), which increases cysta- through inhibition of IL-1b-induced induction of thionine b-synthase activity that removes cyclooxygenases. These neuroprotective func- homocysteine from the methionine cycle. tions suggest that neuroprotectins (through 7. DHA and EPA enhance NO (vasodilator) pro- increased dietary DHA) may be used for thera- duction by altering lipid composition such that peutic management of neurodegenerative dis- endothelial NO synthase is displaced from its eases, especially Alzheimers as well as the normal negative regulator (caveolin-1). cognitive decline associated with aging. Therefore, Some of the benecial effects of omega-3 the anti-inammatory effects of omega-3 fatty PUFAs are further discussed below. acids are mediated through various reactions such (a) n-3 PUFAs and cardiac arrhythmias as reduced chemotactic responses of leukocytes Arrhythmia: irregular or abnormal and level of proinammatory cytokines (via the heartbeat. NF-kB route), as well as increased EPA-dependent Most common fatal arrhythmia is known formation of weakly inammatory or anti- as ventricular brillation (VF). inammatory eicosanoids. Other effects include Studies have shown that VF can be pre- increased DHA- and EPA-dependent formation of vented by n-3 PUFAs in cultured animal anti-inammatory and inammation-resolving heart cells.

7 2.4 Long-Chain Fatty Acids 29 (b) Proposed mechanisms of anti-arrhythmic which is believed to be associated with effect of n-3 PUFAs dietary factors. One of the dietary factors Incorporation and modication of myocyte that have been associated with prostate can- cell membranes by n-3 PUFAs resulting in cer development is ratio of n-6/n-3 PUFAs. modulation of membrane ion channels It is known from various in vitro and animal Prevention of high accumulation of intra- experiments that the two types of PUFA have cellular calcium different and opposite effects on cancer Production of antithrombotic eicosanoids, pathogenesis. This is because n-6 PUFAs which reduces the potential for plaque (linoleic and arachidonic acids) promote formation tumor development while n-3 fatty acids Inuence on cell signaling mediated (a-linolenic acid, EPA, and DHA) suppress through phosphoinositides tumor carcinogenesis. Evidence suggests Induction of different antioxidant that EPA and DHA have antiproliferative enzymes, which reduces level of reactive effects on cancer cells, but direct relation- oxygen species ships to prostate cancer have been mixed (c) Effects of n-3 PUFAs on blood lipid prole with some researchers reporting negative and atherosclerosis while others reported positive associations. In hypertriglyceridemic patients, dietary Some studies have shown that high levels of n-3 PUFAs reduced blood triglycerides dietary linoleic acid (n-6 PUFA) are posi- (TG) by up to 28% after 2 weeks. Longer tively correlated with elevated risk of pros- trials (up to 16 weeks) resulted in up to tate cancer development. Most importantly, 47% reduction in blood TG. it is the balance of n-3 to n-6 PUFAs that is Lower lipoprotein cholesterol, though believed to be the main factor in tumor car- evidence is stronger in animal studies cinogenesis. From epidemiological studies, than in human clinical trials. However, it is known that high n-6/n-3 PUFA ratio is there is increase in HDL cholesterol and associated with prostate cancer risk in men, lowering of total cholesterol content. though the trend was dependent on race of Anti-inammatory effect, which leads to the patient. In white men, high n-6/n-3 PUFA reduced platelet aggregation and inhibi- ratio was associated with risk of overall pros- tion of atherogenesis. Modulation of plate- tate cancer as well as risk of developing let aggregation is mediated through the high-grade form of the tumor. However, in eicosanoid pathway and is not as a result African-American men, high n-6/n-3 PUFA of direct effect of fatty acids on platelets. ratio was associated only with risk of devel- Reduced expression of cell-membrane- oping high-grade form of prostate cancer bound adhesion molecules also contributes tumor. The main mechanism for the benecial to reduced potential for atherogenesis. effects of high dietary n-3 PUFAs on pros- Though the effect on blood pressure is mini- tate cancer is believed to be through the mal, DHA may be a more effective hypoten- competitive inhibition of conversion of n-6 sive agent than EPA through augmentation PUFAs to proinammatory eicosanoids. This of the NO-dependent endothelium-depen- is because n-3 and n-6 PUFAs compete for dent vasodilation. However, increased sh similar enzymes during eicosanoid synthe- consumption leads to high levels of EPA sis; therefore, high levels of n-3 PUFAs will and DHA in the blood, which favors blood reduce catabolism of n-6 PUFAs but increase pressure reduction. formation of anti-inammatory eicosanoids. (d) Effects of omega-3 (n-3) and omega-6 (n-6) High oxidative state coupled with high levels PUFAs on cancer of proinammatory eicosanoids can cause The most commonly diagnosed type damage to critical cellular components such as of cancer among men is prostate cancer, the DNA, which could lead to carcinogenesis.

8 30 2 Bioactive Lipids By reducing the level of proinammatory when compared to omega-3-decient con- eicosanoids in prostate cells, the n-3 PUFAs trol diet that contained corn oil. The FO was have the potential to limit cellular damage only effective in increasing whole-body bone and reduce the risk for carcinogenesis. Using mineral content (~0.5 g) and density (~0.05 adult mice colonocytes, it was shown that g/cm2) in the female Han:SPRD-cy rats. DHA in combination with butyrate was bet- Thus, it seems that the effect of the FO dif- ter than EPA/butyrate in inducing apoptosis. fered according to gender of the rats. The Omega-3 fatty acid-containing sh oil results are important because decreases in has also been shown to induce apoptosis but bone mineral density and lean body mass as confers resistance to oxidation-induced DNA well as increase in adipose tissue mass are damage in colonic cells. Using mice with associated with chronic renal failure and insufcient activity of superoxide dismutase renal transplant. The Han:SPRD-cy is an (SOD2), it was shown that sh oil can autosomal-dominant inheritance that is char- increase oxidative stress and lead to increase acterized by epithelial proliferation, progres- apoptosis of the colon cancer cells. SOD is sive dilatation of nephrons, interstitial one of the main antioxidant enzymes respon- inammation, oxidative injury, and brosis. sible for free radical scavenging; deciency FO also reduced some of these renal disease usually leads to increased mitochondria oxi- markers such as numbers of macrophage dative stress. In normal cells, high oxidative cells and proliferating cell nuclear antigen stress could cause health problems by dam- (inammation) as well as oxidized LDL aging essential nutrients and cellular compo- (oxidative injury) content. Thus, FO may nents. However, in abnormally growing cells serve as a suitable therapeutic intervention like cancer cells, a high oxidative stress tool to reduce the degree of renal could be used to reduce growth and enhance inammation, oxidative injury, and severity apoptosis. This is because as the level of of lean body mass losses associated with reactive oxygen species and lipoperoxides CKD. It has also been demonstrated that increases, eventually the mitochondria dietary intervention through maternal nutri- detoxication capacity is exceeded, and the tion may be effective in reducing pathologi- resultant chronic oxidative stress triggers cal intensity or progression of genetically release of pro-apoptotic factors from the inherited CKD. For example, supplementa- mitochondria into the cytosol. In this case, tion of adult female Han:SPRD-cy rat diets the high level of unsaturated omega-3 fatty with FO led to a 15% decrease in renal cyst acids coupled with the reduced SOD level growth, 12% decrease in cell proliferation, can induce such pro-apoptotic condition of and 15% decrease in oxidative injury in the chronic oxidative stress. offsprings that inherited the disease and (e) Omega-3 PUFAs, obesity, and kidney maintained on FO-free diet. However, the disease renal health benets of FO were increased Obesity continues to be an important risk when the offsprings from FO-fed mothers factor for other chronic metabolic disorders were also maintained on FO diet, postwean- such as insulin resistance (type 1 diabetes), ing. FO-fed Han:SPRD-cy offspring rats hypertension, kidney function impairment, from FO-fed mothers had reduced proteinu- and cancer, all of which can lead to death. In ria (13%), creatinine clearance rate (30%), a rat model (Han:SPRD-cy) of chronic kid- renal brosis (34%), and glomerular hyper- ney disease (CKD), supplementation of diet trophy (23%). FO also mitigated the with omega-3-rich axseed oil (FO) resulted detrimental effects of a high-fat diet on in increased whole-body bone mineral con- renal brosis in polycystic kidney disease tent (~1 g) and density (~0.5 g/cm2) as well mice. The mechanism involved in the as increased lean body mass (~12 g) in males renoprotective effects of FO may be due to

9 2.4 Long-Chain Fatty Acids 31 modulation of eicosanoid synthesis in favor Similarly, the size of adipocyte present in the of less inammatory agents. In FO-fed rats, subcutaneous adipose tissue was inversely related the tissues, organs, and plasma contain to the content of omega-3 fatty acids. In non- higher levels of omega-3 fatty acids, espe- obese, healthy adults with BMI of 2040 kg/m2, cially a-linolenic acid (ALA), which is a plasma omega-3 fatty acid levels were found to precursor for synthesis of longer-chain be inversely proportional to waist and hip cir- omega-3 fatty acids, especially EPA. The cumferences as well as BMI, which indicates a high plasma concentrations of ALA inhibit protective role against obesity for this group of conversion of linoleic acid to arachidonic fatty acids. However, supplementation of diabetic acid (AA); therefore, concentration of EPA mice diet actually exacerbated weight gain, sug- increases while that of AA decreases. EPA is gesting that impaired glucose control may nullify converted slowly to the less vasoactive the weight-reducing effects of omega-3 fatty thromboxane A3, while AA is converted acids. Apart from weight gain prevention, there faster to thromboxane A2, a strong vasocon- has been a limited study on the role of omega-3 strictor, and both fatty acids compete for the fatty acids in established obesity. Dietary omega-3 same metabolic (conversion) enzymes. fatty acid was shown to reduce body fat mass in Therefore, the high levels of EPA lead to mice that were made obese through intake of competitive inhibition of AA conversion, high-fat diet. The loss in weight was attributed to which alters metabolic products in favor of reduced metabolic efciency because of the EPA-derived eicosanoids and reduction in decreased food efciency (lowest weight gain renal injury. Thus, FO may be used in mater- per unit energy intake) in obese mice that whose nal diet to alter eicosanoid production during diet was switched to omega-3-supplemented pregnancy, which can then attenuate disease feed. In humans, the mechanism involved in symptoms associated with inherited CKD in omega-3 fatty acid-induced weight loss has been the offsprings. shown to involve decreased appetite, modulation Various experiments using nondiabetic ani- of lipogenic gene expression, and tissue metabo- mals have conrmed the potential use of omega-3 lism. Human subjects on omega-3-supplemented fatty acids as therapeutic agents to reduce plasma diets have been shown to consume less amount triglycerides and prevent (or treat) excessive of food than equivalents on control diets. It is accumulation of body fat and even weight gain. believed that omega-3 fatty acids can increase In diet-induced obesity, omega-3-supplemented postprandial satiety in overweight and obese rat diets led to a decrease in epididymal fat in individuals, which reduces food intake and calo- addition to attenuation of the increase in retro- ries and which enhances body weight loss and peritoneal fat mass, which were attributed to improved body composition. Increased b-oxida- reductions in number of mature adipocytes and tion of fatty acids through upregulation of mito- adipocyte hypertrophy but not adipocyte number. chondrial carnitine palmitoyl transferase 1 It is important to note that anti-obesity of omega-3 (CPT-1) has been shown to be associated with oil-supplemented diets may be due to the content dietary omega-3 fatty acids. CPT-1 exchanges of DHA because low ratio of EPA/DHA has been coenzyme A for carnitine, which then facilitates shown to promote reduced accumulation of sub- movement of fatty acids into the mitochondria cutaneous fat. However, canola oil has also been for b-oxidation. Mitochondrial expression of shown to reduce accumulation of intra-abdomi- CPT-1 is regulated by peroxisome proliferator- nal fat mass, which was associated with less adi- activated receptors (PPARs) and by AMP- pocyte surface area. Human studies have also activated protein kinase (AMPK). AMPK is shown that abdominal obesity and visceral activated by EPA in adipose tissue and skeletal abdominal fat area are inversely related to muscle, which then leads to upregulation of CPT-1 omega-3 fatty acid content (especially DHA) of expression and increased fatty acid oxidation in perivisceral and omental adipose tissues. the mitochondria. This metabolic regulation of

10 32 2 Bioactive Lipids fatty acid oxidation has been demonstrated in rat There was also reduced mRNA expression level feeding experiments where supplementation of of stearoyl-CoA desaturase (a lipogenic enzyme), the diet with EPA-rich sh (menhaden) oil led to which led to reduced fat synthesis that was asso- signicant increase in skeletal muscle mitochon- ciated with the omega-3-supplemented diet. It drial CPT-1 activity and reduced sensitivity to has been hypothesized that the increased ow of inhibitors when compared to low EPA types of fatty acids into the skeletal muscle for mitochon- oils. The lower sensitivity of CPT-1 ensures drial oxidation could have been due to the fact increased lipid oxidation even in the presence of that omega-3 fatty acids enhance vasodilation other dietary factors that may act as inhibitors. and blood ow. The increased vascular blood Another mechanism proposed for the adipose ow enhances nutrient delivery to the skeletal tissue effects (decreased fat deposition) of muscles, where the nutrients are utilized for omega-3 fatty acids is through increased expres- energy production, but reduces availability of sion of uncoupling protein 3 (UCP-3) mRNA in nutrients for fat synthesis and storage in the adi- the skeletal muscle coupled with increased pose tissue. expression of peroxisomal acyl-CoA oxidase Animal studies have shown the ability of (PACO) in liver, heart, and skeletal muscle. omega-3 fatty acids to alter the metabolic path- However, the PACO pathway is less efcient for ways in skeletal muscle and promote protein energy production because it produces 3040% synthesis to maintain lean muscle mass. Increased more heat and 30% less ATP when compared to protein synthesis required higher metabolic rate mitochondrial b-oxidation. The UCP-3 reduces and fatty acid utilization (to produce ATP), which mitochondrial oxidative phosphorylation could indirectly contribute to reductions in adi- efciency because it induces leakage of protons pose tissue mass. For example, EPA is a known from the mitochondria, which leads to less ATP indirect suppressor of the ubiquitin-proteasome formation but more heat production. Thus, the pathway that is critical for muscle proteolysis to combined effects of PACO and UCP-3 lead to occur. This is because EPA attenuates activation overall reduction in metabolic efciency and of the transcription factor, NF-kb, a positive contributes to decreased stored fat energy (due to modulator of the ubiquitin-proteasome pathway. decreased availability of fatty acids) but increase Increased dietary omega-3 levels promote mus- energy losses in the form of heat. The ability of cle protein synthesis by activating key protein omega-3 fatty acids to reduce adipose tissue synthesis regulatory kinases such as mammalian weight can also be linked to upregulation of (mechanistic) target of rapamycin (mTOR) and intestinal lipid oxidation. This is because dietary S6K. While the specic effects of DHA have omega-3 fatty acids have been shown to increase been reported, the anti-obesity activity of indi- intestinal expression of mRNAs for lipid-oxidiz- vidual omega-3 fatty acids is not fully elucidated. ing agents such as CPT-1a, cytochrome P450 Therefore, the observed benecial effects of 4A10, and malic enzymes. In addition to the omega-3 oils on weight reduction could be due indirect effects on skeletal muscle, intestinal tis- to summation of individual effects or synergistic sue, heart, and liver, there is evidence for the interactions. Overall, the net effect of the inhibi- direct effects of omega-3 fatty acids on adipose tion of protein degradation and promotion of tissue in the form of increased fat oxidative and protein synthesis is decreased substrate for build- decreased fat synthesis capacities in visceral fat ing adipose tissue mass and hence reduced depots. The increased fat oxidation in visceral weight gain. fats resulted from upregulated levels of peroxi- Potential adverse effects of omega-3 fatty some proliferator-activated receptor gamma acids coactivator 1a (PGC-1a) and nuclear respiratory 1. At very high dietary doses (>20 g/day) of factor-1 (NRF-1) that regulate mitochondria bio- omega-3 fatty acids, there is the potential for genesis, as well as CPT-1 that regulates fatty increased bleeding times that is not seen with transfer into the mitochondria for b-oxidation. moderate (25 g/day) consumption.

11 2.4 Long-Chain Fatty Acids 33 COOH C18:2 (c-9, t-11) COOH C18:2 (t-10, c-12) Fig. 2.3 Structures of the two main forms of conjugated linoleic acid (CLA) present in food product 2. High dietary doses may also lead to increase In conjugated linoleic acid, the two double (

12 34 2 Bioactive Lipids Proposed mechanisms of CLA action: there (42%), and brosis (28%). There was also a are contradictory reports in literature on the mode signicant decrease in production of parathyroid of action of CLA, though the following seem to hormone (PTH), which is normally elevated in be the most plausible among several others: this rat model of CKD. PTH is known to induce Indirect antioxidant property through direct bone loss during kidney disease. However, the scavenging of free radicals and inhibition of CLA diet did not produce any signicant effect lipid peroxidation. CLA also upregulates vita- on renal function, which suggests that reductions min E level, a potent antioxidant. Thus, CLA in inammation and oxidative damage markers protects membranes and tissues from destruc- alone may not be sufcient to prevent deteriora- tive oxidative stress by maintaining structural tion of renal functions. In obesity-associated kid- integrity of essential fatty acids, which also ney disease, dietary CLA reduced pathological enhances membrane uidity. symptoms such as kidney weight (7%), glomeruli Inhibition of carcinogen-DNA adduct size (20%), and COX-2 protein levels (39%). In formation. the obese rats, dietary CLA was also effective in Induction of apoptosis. preserving pancreatic islets, improving periph- Modulation of tissue fatty acid composition eral utilization of glucose, and reducing level of and eicosanoid metabolism; CLA inhibits inammatory agents. CLA reduced adipocyte activities of lipoxygenase (leads to reduced size, hepatic steatosis, urinary albumin, and formation of leukotrienes) and cyclooxyge- plasma lipids, but liver function was improved. nase (leads to reduced formation of prosta- glandins). This leads to reductions in signal Conjugated Eicosapentaenoic transduction and cellular activities. Acid (CEPA) Inhibition of hepatic 3-hydroxyl 3-methyl glu- CEPA can be prepared by alkaline treatment of taryl CoA (HMG-CoA) reductase activity, eicosapentaenoic acid (EPA) and has been shown which attenuates cholesterol synthesis with to induce strong and selective in vitro apoptosis benecial effects on plasma cholesterol of tumor cells through a lipid peroxidation mech- content. anism. In animal experiments, CEPA had stron- Increases activity of enzymes involved in fatty ger antitumor effects, especially by preventing acid oxidation (e.g., carnitine palmitoyl trans- development of new blood vessels (angiogenesis) ferase) while decreasing fatty acid synthesis when compared to CLA and EPA. Through this through inhibition of fatty acid synthase mechanism, CEPA acts by cutting off the ow of activity. nutrients into the developing tumor cells; the Affects expression and action of cytokines and malnourished cells will eventually die off and growth factors. scavenged by macrophages. In order to prevent Regulation of certain nuclear receptors angiogenesis, CEPA inhibits secretion and mRNA involved in the control of body weight and expression of matrix metalloproteinases (MMP), adiposity either by reducing level of expres- in particular MMP2 and MMP9 as shown in tis- sion or translational ability of the genes that sue culture experiments. This is because MMP code for these receptors. are a group of enzymes that cause degradation of However, the potential modulation of chronic sub-endothelial basement membrane and sur- kidney disease by CLA isomers has received rounding extracellular matrix, which is then fol- considerable attention, and promising effects lowed by migration and proliferation of the have been demonstrated. In adult male Han:SPRD- endothelial cells to form new vessels. Since MMP cy rats with advanced kidney disease, diet supple- are key factors in angiogenesis, their inhibition mentation with 1% CLA mixture (52% c9, t11: by CEPA limits cell migration and provides a 3% t10, c12: 40% other geometrical isomers) led therapeutic approach to preventing growth and to signicant decreases in oxidative damage metastasis of tumors. It has also been suggested (30%), proliferating cells (28%), inammation that CEPA may act as an antitumor agent by

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